3,4-bis(carbethoxy)-2-isoxazoline and process

ABSTRACT

ABC type compounds are prepared by reacting (A) a nitrite nucleophile with (B) an unsaturated compound such as ethyl acrylate together with (C) an alkylating agent such as ethyl chloroacetate, in the presence of a dipolar aprotic solvent.

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[5 3,4-BllS(CARBETHOXY)-2-lSOXAZOLlNE [58] Fleldof Search 260/307 F AND PROCESS I [75] Inventcr: William M. Hutchinson, Bartlesville, [56] References Cited Okla. UNITED STATES PATENTS Assignee: Petroleum p y 3,591,621 Hutchinson 260/465.4

Bartlesville, Okla. [22] F d J 25 1971 Primary ExammerRaymond V. Rush 1 e an. [21] Appl. No.: 109,582 [57] ABSTRACT Related US Application Data ABC type compounds are prepared by reacting (A) a nitrite nucleophile with (B) an unsaturated compound [62] g g fi Sari 1965 such as ethyl acrylate together with (C) an alkylating agent such as ethyl chloroacetate, in the presence of a [52] U S U 260/307 F dipolar aprotic solvent. [51] Int. Cl C07d 85/16 2 Claims, No Drawings ll 3,4-BKS(CARBlETHOXY)-2-TSOXAZOLHNE AND PRQCESS This application is a divisional application of US. application Ser. No. 507,700, filed Nov. 15, l965, now US, Pat. No. 3,591,621, patented July 6, 1971.

This invention relates to a new and improved method for forming certain multifunctional compounds and the compounds produced thereby.

Heretofore reactions wherein three separate compounds combined to form a single product compound, sometimes called ABC reactions wherein the letters A, B, and C represent each of the three reacting compounds, have been known for some materials. However, for other compounds reactions other than the ABC reaction were more prominent, e.g., an ABB reaction or an AB, polymerization reaction. In fact, reactions other than the ABC reaction have been so prominent that they sometimes came to be the expected reaction. Also heretofore, ABC reactions have generally required more than one reaction step and each step lowered the overall yield of the final ABC compound.

Quite surprisingly, it has been found that when certain nucleophiles (A), certain olefmically and acetylenically unsaturated compounds (B), and alkylating agents (C), all as hereinafter defined, are reacted in the presence of a dipolar aprotic solvent the ABC reaction is prominent and a multi-functional compound is thereby produced in a single reaction step.

There is also provided according to this invention certain novel multifunctional compounds.

Accordingly, it is an object of this invention to provide a new and improved method for making a multifunctional compound. Another object of this invention is to provide novel multifunctional compounds.

Other aspects, objects and the several advantages of this invention will be readily apparent to those skilled in the art from the description and the appended claims.

According to this invention multi-functional compounds are synthesized by contacting under reaction conditions and in the presence of a dipolar aprotic solvent at least one nucleophile selected from the group consisting of the compounds having the formulas )m 2)m LI (R S),,M; at least one compound selected from the group consisting of compounds having formulas and at least one alkylating agent selected from the group consisting of compounds having formulas H i V R o x n I it R -C-C-OR R oso a X-G-C-R R SO X and XCH CH X wherein M is selected from the group consisting of alkali metals, magnesium. and

, kyl and combinations thereof such as alkaryl, aralkyl,

and the like containing from I to 10 carbon atoms, in elusive, preferably alkyl containing from I to 4 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and R and X ischlorine or bromine.

By the term aprotic solvent is meant a solvent which is non-proton (l-l") donating, i.e., is without pro tons to supply to the reaction of this invention. By the term dipolar it is meant a material the molecules of which are non-symmetrical because of the bonding of unlike atoms, and the like so that the centers of the pos itive and negative charge in the molecule do not coincide and the molecule has a positive and negative end, i.e., is an electrical dipole, and as such exhibits an electrical or dipole moment.

The dipolar aprotic solvents of this invention are organic solvents and include N,Ndimethyl amides of the formula wherein R is selected from the group consisting of hydrogen or alkyl radicals containing from I to 3 carbon atoms, inclusive, e.g., N,Ndimethylformamide, l\l,N- dimethylacetamide, and N,N-dime'thylbutyramide, and cyclic sulfones such as trimethylene sulfone and tetramethylene sulfone tetrahydrothiophene-l l-dioxide or sulfolane). Another solvent is N-methyl2- pyrrolidone.

Some examples of nucleophiles which can be employed in this invention are; sodium cyanide, potassium cyanide, lithium nitrite, sodium nitrite, tetramethylammonium nitrite, magnesium nitrite, potassium thiocyanate, cesium cyanide, rubidium iodide, magnesium iodide, sodium iodide, sodium methylate, potassium butoxide, lithium n-decoxide, sodium phenoxide, sodium benzyl mercaptide, the potassium salt of cyclohexanethiol and the like.

Some examples of olefinically and acetylenically unsaturated compounds which can be employed in this invention are: acrylonitrile, methacrylonitrile, methyl acrylate, ethyl methacrylate, phenyl acrylatc, p-tolyl methacrylate, benzyl acrylate, n-decyl acrylate, cyclohexyl methacrylate, vinyl acetate, vinyl butyrate, vinyl benzoate, vinyl 4-methylcyclohexanoate, Z-butyne, 1,2-diphenylacetylene, 1,2-dicyclohexylacetylene, 3,4- heptadiene, 1,3diphenylallene, and the like.

Some examples of alkylating agents which can be employed in this invention are methyl chloroacetate, ethyl bromoacetate, cyclohexyl alpha-chlorodecanoate, n-

decyl alpha-bromophenylacetate, dimethyl sulfate, di-

ethyl sulfate, di-n-decyl sulfate, diphenyl sulfate, decylcycloactyl sulfate, chloroacetone, alpha-chloroethyl phenyl ketone, alpha-chlorobenzyl n-decyl ketone, chloromethyl benzyl ketone, alpha-bromopropyl cyclohexyl ketone, methanesulfonyl chloride, n pentanesulfonyl chloride, benzenesulfonyl chloride, cyclohexanesulfonyl chloride, 4-n-butylbenzenesulfonyl chloride, ethylene dichloride, ethylene dibromide, and the like.

The process of this invention is generally carried out by contacting at least one compound from each of the three above-described groups of compounds substantially at the same time in the dipolar aprotic solvent. The reaction temperature can vary widely, but the reaction is normally effected at a temperature from about 25 to about 200, preferably from about to about 100. The mol ratio of the three reactants can vary widely, but generally the mo] ratios of the nucleophile or the alkylating agent each to the oleflnically or acetylenically unsaturated compound will both range from about 0. 1/1 to about l The mol ratios can be varied depending on the desired product, reaction temperature and many other factors known to those skilled in the art but in many instances, it is preferred to operate under essentially equimolar conditions. Reaction times can also vary widely, ranging from a few minutes, e.g., 3, to several days, e.g., 3. The pressure employed can be autogenous and should be sufficient to maintain the reactants and solvent substantially in the liquid phase.

After the reaction has taken place any well known process for recovering a product from a reaction mixture can be employed such as solvent extraction, crystallization, fractional distillation, vaporization, and the like.

As will be obvious from the examples hereinbelow, a wide variety of multi-functional compounds can be prepared according to this invention. For example, the reaction of sodium cyanide (A), acrylonitrile (B), and ethyl chloroacetate (C) yields 3-cyano-3-cyanomethyl glutaric acid diethyl ester and 3,5,6-tricyanohexanoic acid ethyl ester. These two compounds are novel and are useful as intermediates in that they can be converted to polycarboxylic acids by hydrolysis. They can also be used as plasticizers for polar rubbers, polar resins such as polyvinyl chloride, and in the formation of agricultural chemicals. Other novel compounds formed by this invention which have uses substantially the same as those set forth above are 3,4-bis-(carbethoxy)- 2-isoxazoline, 3-carboxy-5-cyanomethy1-adipic acid triethyl ester, and 2-cyanomethyl-adipic acid dimethyl ester. This invention has the very distinct advantage of being a substantially one-step synthesis which not only has obvious operational advantages but also promotes increased yields of a desired product since it is known that a plurality of steps in any process generally tends to lower the overall yield of the desired product of that process. Also, it is important to note that this invention relates to an anionic polymerization that is aborted in the first or second stage of polymerization and that not only is a two-step process uneconomical compared to the single step of this invention but it is inoperable because an AB product will result when C is not present initially and a BC product cannot be formed since both B and C are electrophiles.

In all of the following examples the reactions were carried out in a standard reaction system designed to exclude moisture and air, provide reflux cooling and external heating and cooling, magnetic stirring, and various means of adding ingredients including powders, liquids, and moisture and air sensitive liquids handled by syringe. The system used comprised a flask with 3 standard tapered necks, and having a 500 milliliter capacity. The flask was fitted with a reflux condenser leading through a drying tube to a conventional bubble counter or gas-sample collector. The flask was fitted with a thermometer, a plug, nitrogen inlet tube or rubber dam for the two other necks, and a magnetic stirring bar. The glass equipment was baked in an oven at 120C or higher overnight. The equipment was purged with nitrogen while cooling. Solvent, oleflnically and acetylenically unsaturated compound, and alkylating agent were injected by syringe into the reactor through an open neck or dam.

The reaction mixture was filtered under anhydrous conditions to remove by-product precipitates and the filtrate distilled at least one time in a Vigreaux column to remove low boiling product and solvent and obtain fractions of the product or products of the reaction.

Conventional gas chromatography, elemental analysis, infrared analysis, and nuclear magnetic resonance techniques were employed in analyzing the product of the reaction and the yields thereof.

EXAMPLE I into the reaction system were charged, in order:

53.0g (1.00 mole) of acrylonitrile (B) 122.5g (1.00 mole) of ethyl chloroacetate (C) ml of sulfolane (solvent) 49.0g (1.00 mole) of sodium cyanide (A) The reaction mixture was heated at a temperature of from to C for 4 hours and thereafter maintained at about 25 C for 18 hours.

The reaction mixture was filtered and the filtrate distilled to yield two products, i.e., 18 grams of 3,4- dicyanobutyric acid ethyl ester (C d-1 N 0 and 38 grams of 3-cyan0-3-cyanomethyl-glutaric acid diethyl ester (C H N O major fractions of each of which by elemental analysis and molecular weight determination by lowering of the vapor pressure of benzene (Osmometer) gave the following results:

3,4-dicyanobutyric acid ethyl ester, boiling range. ll31 15C/15 mm Analysis Found Atom Ratio Calculated for CBH10N2O2 Carbon 57.75% 8.00 57.8% Hydrogen 6.30% 10.32 6.1% Nitrogen 16.4 7: 1.96 16.9%

80.45% Oxygen 19.56% 2.03 19.2% Molecular weight 176 166 3-cyano-3-cyanomethyl-glutaric acid diethyl ester, boiling range l69-l72C/3.0 mm, m, 1.4546

From the above data it can be seen that the products are of the ABC and ABC types, respectively.

EXAMPLE 11 into the reaction system were charged, in order: ml of dimethylformamide (solvent) 10.6g (0.20 mole) of acrylonitrile (B) 24.5g (0.20 mole) of ethyl chloroacetate (C) 9.8g (0.20 mole) of sodium cyanide (A) Compositions Calculated for:

it was maintained at about C for hours. The reaction mixture was filtered and the filtrate distilled to produce l2 grams of the product compound 2-keto-4-oxa- 5-methyl-7,8-dicyano-5-octene. llnfrared spectrum analysis of the product showed bands at 8.6 microns assigned to C-O ether bond and weak bands at 6.2 microns assigned to C=C in enol ether structure. The usual strong bands assigned to nitrile and carbonyl were also present. Elemental analysis and molecular weight obtained by lowering of the vapor pressure of benzene (Osmometer) were as follows:

ml dimethylformamide (solvent) To this stirred mixture at 70C was added at a rate of about onehalf ml/min:

2l.2g (0.40 mole) of acrylonitrile (B).

The reaction mixture was heated at 70C for 6 hours and thereafter maintained at about 25C for 18 hours after which the reaction mixture was filtered and distilled. Distillation data and gas-liquid chromatographic techniques showed 6 grams of 3-cyano-3-cyanomethylglutaric acid diethyl ester were formed and 24 grams of 3,5,6-tricyanohexanoic acid ethyl ester were formed.

The products of this reaction are of the ABC and AB C types, respectively.

EXAMPLE 1v 3,5.6-tricyanohexanoic 3-cyano-3-cyanomethyl- Weight acid ethyl ester glutaric acid diethyl Ratio ll lfl 3 2) (X) 65KB! (C1z 1a 2 4) (y) y Analysis Found 0. 7 17.85 14.6 26.4 17.9 MW 243 219 252 22s 0f 3,5,6-tricyanohexarioic 3Q u 7 Calculated for 2-keto-4-oxa-5-methyl prepared in another experiment carried out similarly Analyss Fmmd P had a boiling point of l55-l60C at 2 millimeters and C, 6190 624 a refractive index n of l.4500. H. /2 6.35 I 6.3 The products of this reaction are of the AB C and ABC types, respectively. 35 o, 17.35 16.7 7 M61. Wt. 235 1 92 EXAMPLE lll Into the reaction system were added in order: v 19.6g (0.40 mole) of sodium cyanide (A) This product is of the ABC type. 49.0g (0.40 mole) of ethyl chloroacetate (C) 40 EXAMPLE V A reaction apparatus (standard except that a mechanical stirrerslipgland was used) was purged with nitrogen by passing it down the condenser and out a powder funnel in one neck of the reaction flask. To it were charged in order:

85.3g (0.50 mole) of p-toluenesulfonylchloride (Eastman white label) (C) 24.5g (0.50 mole) NaCN, ground and dried (A) g of dimethylformamide dried over 4A sieves (solvent) A fast flush was given with N and then flow was reduced while 26.5g (0.50 mole) of acrylonitrile (B) (dried over BaCO was charged. The system was closed and nitrogen was passed through the flask and up the condenser at the rate of one bubble/ l5 sec.

The reaction mixture was heated at a temperature in the range of to C for 8.5 hours after which it was maintained at about 25 C for 42 hours. The reaction mixture was filtered and distilled to yield 12 grams of product boiling in the range of l57 to 200 C at 4 -millimeters, having a melting point of 161 to 166 C, being soluble in water and insoluble in benzene, and being non-polymeric in nature. The non-polymeric nature of the product indicates that, in view of the results of other examples, an ABC reaction took place and not an AB polymerization reaction.

- EXAMPLE V1 Into the reaction system were charged, in order:

26.5 g (0.50 mole) of acrylonitrile (B) 63.5 g (0.50 mole; 1.00 equivalent) of dimethyl sulfate (C) 76.5 g of dimethylformamide (solvent) 24.5 g (0150 mole) of NaCN (A) The reaction mixture was heated at a temperature in the range of 30 to 60 C for 7 hours after which it was maintained at about 25 C for 18 hours. The reaction mixture was filtered and distilled to produce 15 grams ofa product having a boiling point of 90 C at 1.5 millimeters, refractive index n of 1.440, and was nonpolymeric in nature. No trace of methyl cyanide was found in the product thereby eliminating the possibility of an AC reaction and combined with the absence of a polymer, indicating an ABC reaction took place.

EXAMPLE VII Into the reaction system were charged, in order:

24.5g (0.500 mole) of sodium cyanide (A) 52g of dimethylformamide (solvent) 54.3g (0.443 mole) of ethyl chloroacetate (C) 50.0g (0.500 mole) of ethyl acrylate (B) The cyanide was ground and dried for one-half hour. The other ingredients were dried over 4a mole sieves. A prepurified nitrogen flush was used but reduced to ,one bubble/l5 seconds after the last ingredient was added.

The reaction mixture was heated in the temperature range of 70 to 105 C for 6.5 hours after which it was maintained at about 25 C for hours, after which it was heated in the temperature range of 80 to 85 C for 9 hours. maintained at about C for 15 hours, and reheated at 1 10 C for 3 hours. Two products were obtained from filtering the reaction mixture and distilling the filtrate and were analyzed by gas-liquid chromatographic analysis. These products were 3-carboxy-5- cyanomethyl-adipic acid triethyl ester and 3-carboxy- 3-cyanomethyl-glutaric acid triethyl ester. The 3- carboxy-S-cyanomethyl-adipic acid triethyl ester product had a boiling point of 162 C at 1.5 millimeters. A

distillation cut containing a mixture of these two products was analyzed by elemental analysis and the molecular weight was obtained by lowering of the vapor pressure of benzene (Osmometer), the results of which are as follows:

The infrared spectrum of these products showed strong bands characteristic of carboxylate esters and a weak nitrile band.

The glutaric ester is of the ABC type and the adipic ester is of the AB C type.

EXAMPLE VIII 7 Into the reaction system were charged. in order:

43.0g (0.50 mole) of methyl acrylate (B) 54.3g (0.50 mole) of methyl chloroacetate (C) 67g of dimethylformamide (solvent) 24.5g (0.50 mole) of NaCN (A) The reaction mixture was heated in the temperature range of 100 to 1 15 C for 36 hours. thereafter maintained at about 25C for 70hours. The reaction mixture was filtered and distilled. Gas-liquid chromatographic analysis of fractions of the distillate indicated 12 grams of 3 cyanomethyl-glutaric acid dimethyl ester and 19 grams of 2-cyanomethyl-adipic acid dimethyl ester were formed. The adipic acid ester had a boiling point of 126C at 1.5 millimeters. Elemental analysis of a distillate fraction containing both the glutaric acid ester and the adipic acid ester was carried out, the results being as follows:

The infrared spectrum of this fraction showed strong nitrile and carboxylate ester bands.

The glutaric ester is a decarboxylated ABC product and the adipic ester is decarboxylated AB C product.

EXAMPLE 1X lnto the reaction system were added. in order:

47.5g of dimethylformamide (solvent) 50.0g (0.50 mole) of ethyl acrylate (B) 61.3g (0.50 mole) of ethyl chloroacetate (C) After chilling to 2 C the following was added in one portion:

34.5g (0.50 mole) of sodium nitrite (A).

The reaction mixture was heated at C for 3 hours after which it was filtered and distilled to yield 30 grams of 3.4-bis (carbethoxy)-2-isoxazoline having a boiling point of 1 18 to 123 C at 2 millimeters and a refractive index (r1 of 1.4669.

Elemental analysis and molecular weight by lowering of the vapor pressure of benzene (Osmometer") are given for the product:

Color tests on the product for nitro nitrite and nitroso groups on the carbon atom were negative. The infrared spectrum of the product showed a strong band at 6.3

microns assigned to N=C in the isoxazole ring in addition to strong carboxylate ester bands. The nuclear magnetic resonance spectrum of the product showed a triplet at 275-305 cps, a doublet at 185-205 cps plus the usual peaks at 220255 cps and triplet'at 60-90 cps characteristic of ethyl carboxylate esters. These observations are in agreement with:'

This is a self-condensed ABC product.

' EXAMPLE x The reaction mixture was heated at 65C for 7 hours and thereafter maintained at about C for 96 hours.

The reaction mixture was then filtered and the tilthe acrylonitrile reacted, a color developed, and a fine precipitate formed, thereby indicating, in view of the -results of other examples, an ABC reaction.

EXAMPLE xi Into the reaction system were charged, in order: 54.3g (0.50 mole) of methyl chloroacetate (C) 430;; (0.50 mole) of methyl acrylate (B) 65.0g of dimethyl formamide (solvent) 405g (0.50 mole) of NaSCN (ground, dried 0.5 hour at 200C) (A) The reaction mixture was heated to 60-64C for 5 /2 hours, then maintained at about 25C for 18 hours, thereafter heated at 70C for 9 hours, tained at about 25C for 18 hours.

The reaction mixture was filtered and then distilled. No polymeric substance was found in the reaction product, an exothennic reaction occurred, and a color 1 developed, thereby indicating, in view of the results of other examples, an ABC reaction.

Reasonable variations and modifications are possible within the scope of this disclosure without departing from the spirit and scope thereof.

I claim:

11. 3,4-Bis-(carbethoxy)-2-isoxazoline.

2. A method for forming 3,4-bis-(carbethoxy)-2- isoxazoline which comprises the steps of reacting (A) sodium nitrite, (B) ethylacrylate, and (C) ethylchlor oacetate, in the presence of dimethylformamide under reaction conditions at a temperature of 100C and a pressure sufficient to maintain a substantially liquid phase, with the exclusion of air and water, and wherein trate distilled. No polymer product was obtained, all of the mole ratios of said (A) to said (B) and of said (C) 'to said (B) are each about 1:1, thereby forming said 3,-

and then main- 

1. 3,4-BIS-(CARBETHOXY)-2-ISOXAZOLINE.
 2. A method for forming 3,4-bis-(carbethoxy)-2-isoxazoline which comprises the steps of reacting (A) sodium nitrite, (B) ethylacrylate, and (C) ethylchloroacetate, in the presence of dimethylformamide under reaction conditions at a temperature of 100*C and a pressure sufficient to maintain a substantially liquid phase, with the exclusion of air and water, and wherein the mole ratios of said (A) to said (B) and of said (C) to said (B) are each about 1:1, thereby forming sAid 3,4-bis-(carbethoxy)-2-isoxazoline. 